Female mammals with chronic anovulation who experience withdrawal bleeding after progesterone administration are said to be in a state of "estrus" due to the acyclic production of estrogen, largely estrone, by extraglandular aromatization of circulating androstendione. The most common terms for this disorder are "polycystic ovary syndrome" (PCOS) and "polycystic ovarian disease" (PCOD).
PCOS is characterized by infertility, hirsutism, obesity, particularly central obesity, which is characterized by an increased waist/hip ratio), acne and/or amenorrhea or oligomenorrhea. When spontaneous uterine bleeding occurs in patients with PCOS; it is unpredictable with respect to time of onset, duration, and amount, and on occasion the bleeding can be severe. The dysfunctional uterine bleeding is usually due to estrogen breakthrough.
PCOS, which may be transmitted as an autosomal dominant or X-linked trait, was originally described as characterized by enlarged, polycystic ovaries, but the syndrome and its accompanying endocrine abnormalities are now known to be associated with a variety of pathologic findings in the ovaries, only some of which result in enlargement of the ovaries and none of which are pathognomonic. The most common finding is a white, smooth, sclerotic ovary with a thickened capsule, multiple follicular cysts in various stages of atresia, a hyperplastic theca and stroma, and rare or absent corpora albicins. Other ovaries have hyperthecosis in which the ovarian stroma is hyperplastic and may contain lipid-laden luteal cells. Thus, the diagnosis of PCOS is a clinical one, based on the coexistence of chronic anovulation and varying degrees of androgen excess.
In most women with PCOS, menarche occurs at the expected time, but uterine bleeding is unpredictable in onset, duration and amount. Amenorrhea ensues after a variable time, although primary amenorrhea occurs in some women. Signs of androgen excess, such as hirsutism, usually become evident around the time of menarche.
One proposed mechanism for the initiation and perpetuation of chronic anovulation suggests that PCOS originates as an exaggerated adrenarche in obese girls. The combination of elevated adrenal androgens and obesity would result in increased formation of extraglandular estrogen and lead to an acyclic positive feedback on LH secretion and negative feedback on FSH secretion so that characteristic LH/FSH ratios in plasma would be greater than 2. The increased LH levels could then lead to hyperplasia of the ovarian stroma and theca cells and increased androgen production, which in turn would provide more substrate for peripheral aromatization and perpetuate the chronic anovulation. In the advanced state of PCOS, the ovary is the major site of androgen production, but the adrenal may continue to secrete excess androgen as well. The greater the obesity, the more this sequence will be perpetuated because adipose (fat) tissue aromatizes androgens to estrogens, which in turn exaggerates inappropriate LH release by positive feedback.
Thus, the fundamental defect in PCOS is viewed as one of inappropriate signals to the hypothalamus and the pituitary. In fact, the hypothalamus-pituitary axis responds appropriately to high levels of estrogen, and ovulation can be induced with anti-estrogens such as clomiphene citrate. Increased levels of plasma endorphins and inhibin contribute to the perpetuation of this defect.
The concept that the fundamental defect in PCOS is one of inappropriate signals is supported by the empirical evidence from the ovaries. More specifically, ovarian follicles from women with PCOS have low aromatase activity, but normal aromatase can be induced when the follicles are treated with FSH. Thus, the anovulation is not due to an intrinsic abnormality in the ovary, but rather results from FSH deficiency and LH excess.
Conventional treatment of PCOS may be directed at interrupting this self-perpetuating cycle. Such treatments include: wedge resection or oral contraceptives, to decrease ovarian androgen secretion; weight loss, to decrease peripheral estrogen formation; or treatment with clomiphene, human menopausal gonadotropin (hMY), or LHRH (gonadorelin), to enhance FSH secretion.
During the past decade, it has become apparent that many women suffering from PCOS are characterized by hyperinsulinemia. Both obese and non-obese women with PCOS are more hyperinsulinemic than age and weight matched normal women (Ciraldi et al., J Clin. Endocrinol. Metab. 75:577-583 (1992); Dunaif et al., J Clin. Invest. 96:801-810 (1995)). Hyperinsulinemia is a feature of PCOS not only in the United States, but also in other societies.
For example, studies conducted in the United States, Japan and Italy demonstrated that women with PCOS all manifested hyperinsulinemia when compared to their respective normal counterparts (Carmina et al, J Obstet. Gynecol. 167:1807-1812 (1992)). This common finding across multiple ethnic groups suggests that hyperinsulinemia represents a fundamental feature of PCOS in many affected women.
More important, recent studies (Nestler et al., New Engl. J Med. 335:617-623 (1996); Jakubowicz et al, J Clin. Endo. Metab. (1997)(in press); Dunaif et al., J Clin. Endo. Metab. 81:3299-3306 (1996)) have demonstrated that excess androgen concentrations are decreased when hyperinsulinemia is reduced pharmacologically, with either metformin or troglitazone, or by dietary means.
All of these observations lead to the conclusion that correction of the underlying hyperinsulinemia may be an important target for clinical intervention in PCOS.